Anti-Inflammatory Effects of Epoxyeicosatrienoic Acids

Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
International journal of vascular medicine 07/2012; 2012(1):605101. DOI: 10.1155/2012/605101
Source: PubMed


Epoxyeicosatrienoic acids (EETs) are generated by the activity of both selective and also more general cytochrome p450 (CYP) enzymes on arachidonic acid and inactivated largely by soluble epoxide hydrolase (sEH), which converts them to their corresponding dihydroxyeicosatrienoic acids (DHETs). EETs have been shown to have a diverse range of effects on the vasculature including relaxation of vascular tone, cellular proliferation, and angiogenesis as well as the migration of smooth muscle cells. This paper will highlight the growing evidence that EETs also mediate a number of anti-inflammatory effects in the cardiovascular system. In particular, numerous studies have demonstrated that potentiation of EET activity using different methods can inhibit inflammatory gene expression and signalling pathways in endothelial cells and monocytes and in models of cardiovascular diseases. The mechanisms by which EETs mediate their effects are largely unknown but may include direct binding to peroxisome proliferator-activated receptors (PPARs), G-protein coupled receptors (GPCRs), or transient receptor potential (TRP) channels, which initiate anti-inflammatory signalling cascades.

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    • "P450s also mediate one of the three major pathways of arachidonic acid (AA) metabolism, producing hydroxyeicosatrienoic acids (HETES) and epoxyeicosatrienoic acids (EETs). EETs, which are readily converted to dihydroxyeicosatrienoic acids (DiHETEs) by epoxide hydrolases, are well-known anti-inflammatory mediators262728. In in vitro studies, we detected a number of AA metabolites in small intestinal microsomal reactions with AA, including 5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET, 5,6-DiHETE, 8,9-DiHETE, 11,12-DiHETE,14,15-DiHETE, 19-HETE and 20-HETE, of which 11,12-DiHETE and 14,15-DiHETE appeared to be the most abundant (data not shown); the rates of metabolite formation were substantially lower in IE-Cpr-null mice than in WT mice, thus confirming role of microsomal P450 enzymes in intestinal AA metabolism. "
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    ABSTRACT: Cytochrome P450 (P450) enzymes are a superfamily of heme-containing enzymes involved in the metabolism of various endogenous compounds, including retinoids, glucocorticoids, and eicosanoids, that are postulated to participate in the maintenance and/or development of inflammatory and immune reactions in the intestinal mucosa. To investigate the role of P450 enzymes in intestinal inflammation and immunity, we took advantage of IE-Cpr-null mice, which are deficient in intestinal epithelium of NADPH-cytochrome P450 reductase (CPR), the obligate redox partner of all microsomal P450 enzymes. We report that IE-Cpr-null mice, following an acute toxin challenge, had higher levels of pro-inflammatory chemokines and increased tissue damage compared to wild-type mice. IE-Cpr-null mice had normal Peyer's patch numbers and elicited normal secretory IgA (SIgA) responses. However, SIgA baseline levels in IE-Cpr-null mice were consistently elevated over WT littermates. While neither retinoic acid nor glucocorticoid levels in serum and intestinal homogenates were altered in IE-Cpr-null mice, basal levels of arachidonic acid metabolites (11,12-DiHETE and 14,15-DiHETE) with known anti-inflammatory property were significantly lower compared to WT controls. Overall, these findings reveal immunological and metabolic changes resulting from a genetic deficiency in CPR expression in the intestine, and support a role for microsomal P450 enzymes in mucosal homeostasis and immunity.
    Scientific Reports 07/2014; 4:5551. DOI:10.1038/srep05551 · 5.58 Impact Factor
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    • "While the role of CYP-derived oxylipins in platelets is unknown, based on their signaling properties in other cells, it is hypothesized that they may have a signaling role in platelets as well. The EET receptor remains to be identified, however, evidence suggests that EETs can signal through GPCRs (Thomson et al., 2012). Follow-up studies are required to determine whether platelets express cyp-oxylipin receptors and if so what role they play in the regulation of platelet aggregation. "
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    ABSTRACT: The prevalence of cardiovascular disease (CVD), the leading cause of death in the US, is predicted to increase due to the shift in age of the general population and increase in CVD risk factors such as obesity and diabetes. New therapies are required to decrease the prevalence of CVD risk factors (obesity and diabetes) as well as reduce atherothrombosis, the major cause of CVD related mortality. Oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids, play a role in the progression of CVD risk factors and thrombosis. Aspirin, a cyclooxygenase-1 inhibitor, decreases atherothrombotic associated mortality by 25%. These potent effects of aspirin have shown the utility of modulating oxylipin signaling pathways to decrease CVD mortality. The role of many oxylipins in the progression of CVD, however, is still uncertain or controversial. An increased understanding of the role oxylipins play in CVD risk factors and thrombosis could lead to new therapies to decrease the prevalence of CVD and its associated mortality.
    Frontiers in Pharmacology 01/2014; 4:176. DOI:10.3389/fphar.2013.00176 · 3.80 Impact Factor
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    ABSTRACT: Cytochrome p450 (CYP)2J2 is an epoxygenase enzyme that metabolises arachidonic acid to epoxyeicosatrienoic acids (EETs). EETs are inactivated by soluble epoxide hydrolase (sEH), which converts them in to their corresponding dihydroxyeicosatrienoic acids (DHETs). CYP2J2 is highly expressed in cardiovascular tissue including the heart and vascular endothelial cells. CYP2J2 and the EETs it produces have been shown to have a diverse range of effects on the vasculature, including the regulation of inflammation, vascular tone, cellular proliferation, angiogenesis, and metabolism. This review will examine these established and emerging roles of CYP2J2 in the biology of vascular endothelial cells.
    Prostaglandins & other lipid mediators 03/2013; 107. DOI:10.1016/j.prostaglandins.2013.02.003 · 2.38 Impact Factor
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